The search for new therapeutic agents has been greatly aided in recent years by better understanding of the structure of enzymes and other biomolecules associated with target diseases. One important class of enzymes that has been the subject of extensive study is the protein kinases. Many diseases are associated with abnormal cellular responses triggered by protein kinase-mediated events. These diseases include autoimmune diseases, inflammatory diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease or hormone-related diseases. Accordingly, there has been a substantial effort in medicinal chemistry to find protein kinase inhibitors that are effective as therapeutic agents.
Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase comprised of α and β isoforms that are each encoded by distinct genes (Coghlan et al., Chemistry & Biology, 7, 793-803 (2000); Kim and Kimmel, Curr. Opinion Genetics Dev., 10, 508-514 (2000)). The threonine/serine kinase glycogen synthase kinase-3 (GSK-3) fulfills a pivotal role in various receptor-linked signalling pathways (Doble, B W, Woodgett, J R J. Cell Sci. 2003, 116:1175-1186). Dysregulation within these pathways is considered a crucial event in the development of several prevalent human disorders, such as type II diabetes (Kaidanovich O, Eldar-Finkelman H, Expert Opin. Ther. Targets, 2002, 6:555-561), Alzheimer's disease (Grimes C A, Jope R S, Prog. Neurobiol. 2001, 65:391-426), CNS disorders such as manic depressive disorder and neurodegenerative diseases, and chronic inflammatory disorders (Hoeflich K P, Luo J, Rubie E A, Tsao M S, Jin O, Woodgett J, Nature 2000, 406:86-90). These diseases may be caused by, or result in, the abnormal operation of certain cell signalling pathways in which GSK-3 plays a role.
GSK-3 has been found to phosphorylate and modulate the activity of a number of regulatory proteins. These proteins include glycogen synthase which is the rate limiting enzyme necessary for glycogen synthesis, the microtubule associated protein Tau, the gene transcription factor β-catenin, the translation initiation factor e1F2B, as well as ATP citrate lyase, axin, heat shock factor-1, c-Jun, c-Myc, c-Myb, CREB, and CEPBα. These diverse protein targets implicate GSK-3 in many aspects of cellular metabolism, proliferation, differentiation and development.
Currently, inhibition of GSK-3 may represent a viable strategy to develop novel medicinal entities for the treatment of such unmet diseases (Martinez A, Castro A, Dorronsoro 1, Alonso M, Med. Res. Rev., 2002, 22:373-384) through insulin mimicry, tau dephosphorylation and amyloid processing, or transcriptional modulation respectively.
In the State of the Art, some compounds containing an urea group have already been described as having GSK-3 inhibitory properties. This is the case, for example, of publications WO03/004472, WO03/004475 and WO03/089419. These publications refer each one to a very broad number of compounds defined by a Markush structure, said structure being big and complex, this circumstance making their preparation more complicated and increasing the probability of reactivity of the compounds. Particularly, these compounds pertain to structural subgroups such as substituted thiazole compounds and heterocyclic amines. These compounds may contain, among many other groups, an urea functional group. These compounds are generally said to have inhibitory effects on GSK-3, and thus potential activity in the treatment and prevention of a series of diseases related to GSK-3, such as dementias, diabetes and mood disorders. Nevertheless, no results regarding GSK-3 inhibition for any particular compounds are included in any of the above-mentioned publications; that is, neither for those comprising an urea functional group any results really proving any activity of these urea derivatives are shown.
On the other hand, Publication WO03/004478 and article “Structural Insights and Biological Effects of GSK-3 specific Inhibitor AR-A014418”, J. Biol. Chem., 278 (46), 2003 deal with one particular urea, 4-(4-methoxybenzyl)-N′-(5-nitro-1,3-thiazol-2-yl)urea; this urea indeed has a much smaller and simpler structure than the above mentioned ureas. It is described as having GSK-3 inhibitory properties, and thus as having potential activity for treating and/or preventing numerous conditions associated with glycogen synthase kinase 3. Nevertheless, it is not clear whether the GSK-3 inhibitory effect is due to the urea itself or to the nitro-thiazole, as heterocyclic compounds have been described as having GSK-3 inhibitory properties, see for example above-mentioned WO03/089419.
Some other ureas have been described in relation to the treatment of neurological disorders, but in relation with completely different methods of action, for example WO00/06156, wherein the disclosed ureas are described to be potentiators of glutamate receptor function.
There is therefore still a need to find good GSK-3 inhibitors, being both effective and selective, and having good “drugability” properties, i.e. good pharmaceutical properties related to administration, distribution, metabolism and excretion. An additional advantage would be to find compounds with simple, stable structures, being easy to be prepared by ordinary proceedings known to the skilled person.